Assistant Professor University of California, San Francisco, School of Medicine San Francisco, California, United States
Background: Neonatal hypoxic-ischemic encephalopathy (HIE) disproportionately affects low- and middle-income countries (LMIC) where nearly 96 % of affected infants reside. The current standard of care in high income countries, therapeutic hypothermia, is frequently ineffective in this setting, likely because much of the injury may be occurring significantly before delivery due to subacute ischemia. Alternate therapies specifically targeting HIE pathogenesis in LMICs are currently lacking. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal caffeine administration in near-term lambs following global ischemic injury to support the development of earlier treatment strategies targeting the fetus in utero as well as the infant postnatally. Objective: To investigate the pharmacokinetics, safety, and efficacy of perinatal caffeine administration in near-term lambs subjected to global ischemic injury. Design/Methods: Lambs of both sexes (n=21 caffeine and 21 placebo, 141-143 days) were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion (UCO) model. Pregnant ewes were randomly assigned to receive either 1gm intravenous caffeine citrate or placebo immediately prior to injury and their lambs to receive either 20 mg/kg caffeine citrate following resuscitation and 10 mg/kg/day for two days thereafter. Outcome measures were assessed over a six-day period. Results: Perinatal caffeine administration demonstrated excellent placental transport kinetics and was well tolerated with serum levels matching currently used upper levels in neonates. Caffeine administration resulted in a systemic immunomodulatory effect, demonstrated by significant reductions in pro-inflammatory IP-10 levels. Treated lambs demonstrated improved neurodevelopmental outcomes while histological analysis revealed that caffeine reduced gray matter injury and attenuated inflammation in the cingulate and parasagittal cortex.
Conclusion(s): Perinatal caffeine administration is well tolerated, attenuates systemic inflammation and contributes to improvements in certain histological and neurological outcomes in an ovine model of HIE.
